Respiratory disease encompasses pathological conditions that affect the organs and tissues responsible for respiration, such as the bronchi, lungs and so on, typically with the accompaniment of inflammation. Representative inflammatory respiratory diseases are acute upper respiratory tract infection, mediated by Th1 or Th17 immune response, chronic obstructive pulmonary disease (COPD), chronic sinusitis, allergic rhinitis, chronic lower respiratory tract infection, chronic bronchitis, emphysema, pneumonia, bronchial asthma, sequelae of pulmonary tuberculosis, acute respiratory distress syndrome, cystic fibrosis, and pulmonary fibrosis.
Inflammatory respiratory diseases may be treated or prevented by suppressing respiratory inflammation. However, there has still been a need for drugs which have a therapeutic effect on inflammatory respiratory diseases that is satisfactory.
The body has evolved to develop defense mechanisms against bacterial infection by N-formylmethionyl peptides produced from bacteria as chemoattractants for macrophages, especially neutrophils and monocytes. Among N-formyl peptides, f-Met-Leu-Phe (FMLP) was identified to have the most potent ability to induce phagocytosis and lysosomal enzyme release [Showell et al., J, Exp. Med, 143:1154-1169, 1976]. Since then, synthetic tetrapeptides, particularly, f-Met-Ile-Phe-Leu (SEQ ID NO: 29) and f-Met-Leu-Phe-Ile (SEQ ID NO: 30) were also reported to induce neutrophil reactions [Rot et al., Proc. Natl, Acad, Scie, USA 84:7967-7971, 1987]. In the beginning, the functions of the peptides were attributed to 1) N-terminal formyl group, 2) the side chain of methionine, and 3) the side chains of leucine and phenylalanine.
N-formyl peptide receptor (FPR) possesses seven hydrophobic transmembrane domains that are linked to adjacent ones via hydrophilic sequences located either within the cell or in an extracellular space (Murphy, Annu. Rev. Immunol. 12: 593-633, 1994). The first and the third intracellular loop are relatively small, consisting of five and six amino acid residues, respectively. While the carboxyl terminus is exposed in the cell, the N-terminus is exposed in the extracellular space. In addition, the intracellular sequences comprise a G protein-coupling region (essential for the function of the receptor) and a potential phosphorylation region.
The six amino acid sequence Trp-Lys-Tyr-Met-Val-d-Met (WKYMVm; SEQ ID NO: 4) is known to bind to FPR (formyl peptide receptor) and its analogues FPRL1 (formyl peptide receptor-like 1). Such a short peptide sequence shows high affinity for a broad spectrum of receptors and can be effectively used to study FPR- or FPRL1-mediated signaling [International Patent Publication No. WO/2005/077412; Le, Y., Oppenheim, J. J., and Wang, J. M. (2001) Cytokine Growth Factor Rev. 12, 91-105); Bae Y S et al., Journal of Leukocyte Biology 71(2): 329-338 (2002); Christophe T et al., Journal of Biological Chemistry 276(24): 21585-21593 (2001); He R et al., Journal of Immunology 165(8): 4598-4605 (2000); Li B Q et al., Blood 97(10): 2941-2947 (2001); Seo J K et al., Journal of Immunology 158(4): 1895-1901 (1997); Seo J K et al., Clinical Biochemistry 31(3): 137-141 (1998)].
However, there are not many examples in which peptides binding to FPR or its analog receptor are used to treat diseases. WKYMVm (SEQ ID NO: 4) was reported to increase the protective system against bacteria in patients with leukemia or cancer who had received chemotherapy [H. Kim et al., Leukemia Research 32(5):717-725 (2008); H. Kim et al., Experimental Hematology 34(4):407-413 (2006)]. There is disclosed a method for modulating immune responses using WKYMVm and peptides with similar amino acid sequence [WO2005/077412]. However, nowhere has the application of WKYMVm or other peptides binding to FPR or its analog receptors to the suppression of respiratory inflammation been disclosed in previous documents. Particularly, the fact that the administration of such peptides via the respiratory tract rather than via other routes can significantly suppress respiratory inflammation has not yet been reported.